Chris Masterjohn, PhD shared his points about Insulin Resistance Isn't All About Carbs and Insulin.

Insulin Resistance Isn’t All About Carbs and Insulin

Facebook
Facebook
Twitter
Visit Us
Instagram
SOCIALICON
Chris Masterjohn, PhD shared his points about Insulin Resistance Isn't All About Carbs and Insulin.

In episode 23, I explained why ketogenesis isn't all about carbs and insulin. Here in episode 25, I explain why insulin resistance isn't all about carbs and insulin. If that doesn't sound crazy, let me put it this way: forget carbs; I'll even say insulin resistance isn't all about insulin.

We start with a riddle: what do obesity, exercise, cigarette smoking, and diets rich in fruits and vegetables all share in common? Hint: it's a centrally important physiological response to each of them that mediates their health effects.

In the course of answering this riddle, I explain the underlying physiology that I consider most important to “insulin resistance” and why I believe insulin resistance is best viewed as subset of something far more important. I conclude by outlining practical strategies to prevent and reverse it.

Listen on ITunes or Stitcher.
Click here to stream.
Right-click (control-click on the Mac) here and choose “save as” (“save link as” on Mac) to download.
Subscribe in your own reader using this RSS feed.

Read the show notes.
Read the transcript.
Leave a comment.

Read on for the show notes.

This episode is brought to you by US Wellness Meats. I use their liverwurst as a convenient way to make a sustainable habit of eating a diversity of organ meats. They also have a milder braunschweiger and an even milder head cheese that gives you similar benefits, as well as a wide array of other meat products, all from animals raised on pasture. Head to grasslandbeef.com and enter promo code “Chris” at checkout to get a 15% discount on any order that is at least 7 pounds and is at least $75 after applying the discount but under 40 pounds (it can be 39.99 lbs, but not 40). You can use this discount code not once, but twice!

Show Notes for Episode 25

In this episode, you will find all of the following and more:

  • 03:35      The riddle   
  • 06:30      Why would an individual cell “decide” to stop responding to insulin?
  • 10:05      The limitations of using blood insulin and glucose concentrations as a primary metric of insulin resistance are similar to the limitations of assessing your level of “boss resistance” by the number of phone calls you decline from your boss when you skip work.
  • 12:25       Why your pancreas is sort of like your boss.
  • 14:37        Reactive oxygen species (ROS) are central to the physiology.
  • 17:52       ROS inhibit aconitase and shunt internal energy toward fat storage.
  • 19:55       ROS inhibit further intake of energy.
  • 20:34      ROS inhibit fatty acid uptake into mitochondria.
  • 21:53       ROS inhibit glucose uptake.
  • 22:35      ROS increase the expression of the entire antioxidant system and xenobiotic defense system.
  • 24:53      Subbing players on the field in team sports provides a useful analogy to understand why ROS-mediated inhibition of cellular energy uptake is health-promoting when other cells can fill in.
  • 28:30     Insulin resistance isn't all about insulin; some responses to cellular energy overload antagonize insulin; others mimic insulin.
  • 30:46      Back to the riddle.
  • 31:05      Obesity vs. exercise
  • 32:50      AMPK activation makes the net effects of ROS in exercise very different from obesity.
  • 37:30      Micronutrient intake determines whether net effects of ROS support antioxidant defense.
  • 37:55     Glutathione synthesis depends on both nutrients and insulin sensitivity and stimulation.
  • 41:10      Insulin resistance isn't all about ROS. It's about the context in which ROS operate.
  • 42:30    The net hormetic pro-oxidant effects of fruits and vegetable polyphenols.
  • 46:53     The net toxic pro-oxidant effects of cigarette smoking.
  • 49:49     Again, net effects of ROS aren't about ROS; their about the context in which ROS operate.
  • 51:00     Nutrient density as a practical strategy in insulin resistance.
  • 56:15     Body composition as a practical strategy in insulin resistance.
  • 50:23     Low-carbohydrate diets as a useful practical strategy for body composition, with potential limitations in the long-term because of the importance of carbohydrates for antioxidant defense.

Links and Research Related to Episode 25

The original Twitter exchange that inspired this podcast is only available in bits and pieces, but here is quite a bit of it.

My weight loss story and my practical tips for weight loss in episode 23.

My AHS 2012 presentation, Oxidative Stress and Carbohydrate Intolerance

Redefining Oxidative Stress by Dean Jones

Radical-Free Biology of Oxidative Stress by Dean Jones

Aconitase as the link between energy metabolism, iron homeostasis, and redox status

Voltage-dependent anion channel (VDAC) as mitochondrial governator — Thinking outside the box

A review and another review on Nrf2

Current understanding of metformin mechanisms

Oxidative stress causes insulin resistance in exercise-induced muscle damage

Nrf2 mediates ROS-induced mitochondrial biogenesis in response to exercise

Review on redox signaling pathways in exercise.

Transcript of Episode 25

This transcript was generously provided by Cassandra Barns.

This is Chris Masterjohn, and you're listening to episode 25 of Mastering Nutrition, where we will be talking about why insulin resistance isn't all about carbs and insulin.

This episode is brought to you by US Wellness Meats. I discovered this company at Paleo f(X) this spring and I fell in love with them as soon as I tried their liverwurst. For years I've known that I feel best when I eat a diversity of organ meats like liver and heart. I have a clearer mind, feel more energetic, and my energy is much more stable between meals. But it is so hard and so time-consuming to make a sustainable habit out of preparing and cooking organ meats. US Wellness liverwurst is 15% heart, 15% kidney, 20% liver, with the remainder grass-fed beef. That's a whopping half organ meat. It takes zero time to prepare, tastes great and finally makes consuming a diversity of organ meats a habit that I can easily sustain. But just because I'm obsessed with their liverwurst doesn't mean it'll turn out to be your favorite. US Wellness makes an even milder braunschweiger that's 35% liver, 65% beef. And if you have a really sensitive palate and just want to get your feet wet with organ meats, their head cheese delivers the mildest taste with 15% heart, 15% tongue, no liver, and the remainder beef. They also sell an incredible array of other meat products in practically any cut you could want, all from animals raised on pasture. Now, this isn't just about high-quality grass-fed meat products that can up your nutritional game and save you time in the morning. It's also about saving money, and that's because I worked out a special deal for you. As a member of my audience, you can go to grasslandbeef.com and order whatever you want, and as long as your total order is at least 7 pounds and, after applying the discount is at least $75, and as long as it’s under 40 pounds, you just enter the promo code “Chris” at checkout. Putting my name in the box earns you 15% off your order, and since you can order up to 39.9999 pounds of meat at that discount, you can potentially save a lot of money. If you're on the fence or not ready for a big order, don't worry. You can use the promo code “Chris” not once, but twice. So, order the minimum your first time, and if you love this stuff as much as I do, order the max the second time around and get the same level of discount. Or just max out your order both times and get just shy of 80 pounds of meat at the discounted price. Either way, head over to grasslandbeef.com and make sure you enter “Chris” at checkout to get the discount.

If I blew your mind when I told you that ketogenesis isn't all about carbs and insulin, then I should shortly be blowing your mind now when I tell you that insulin resistance isn't all about carbs and insulin. But if that doesn't blow your mind, let's try this.

03:35 The riddle  

I want to pose to you a riddle. And that riddle is: what to do the four things that follow all share in common? Number one, obesity; number two, exercise; number three, cigarette smoking; number four, the consumption of a diet high in fruits and vegetables. And I'll give you a hint: it is not something obscure. It is not something out of left field. It is not something that is funny. It's actually something that is completely central to their physiology. So what is the one thing at the molecular cellular level that cigarette smoking, obesity, fruits and vegetables, and exercise are all doing that's the same?

Alright, I'll answer that at the end of the podcast. But want to take it back to the original question. And this originated from a Twitter conversation that I will link to in the show notes. The show notes can be found at ChrisMasterjohnPhD.com/25. And this was: what is the cause of insulin resistance? And is it insulin? And so one of the things that was brought up in this conversation was that how could it not be the case that if you have chronic overexposure to insulin, that you won't get insulin resistance as a result of that – it's a classic response to have the down-regulation of sensitivity to a hormone in the presence of repeated high concentrations of that hormone. And I would say yes, that's sort of on the one hand obvious with any basic background in physiology, and also kind of irrelevant. And I would say that insulin resistance is not really – it shouldn't be the thing that we're talking about. It is a subset of responses that are reflective of a much broader situation that's occurring. And there are many facets to this, but I think that a large portion of those facets can all fall under the concept of cellular energy overload. And that's what I'm going to focus on in this podcast.

I think there's one other class of responses that's due to tissue energy overload, and that's part of what's driving the systemic inflammatory response that actually tells other cells throughout the body to stop responding to insulin, or to stop taking up energy.

06:30 Why would an individual cell “decide” to stop responding to insulin?

But today I want to focus on why would an individual cell “decide” to stop responding to insulin? And so I want to also start with this basic premise that I think is – of course I'm anthropomorphizing a little bit here for the sake of communicating the principle, but I think I'm doing so in a way that preserves the accuracy of what we're talking about. But I would say that each cell has to make executive decisions about how – whether and how it will respond to hormones. So endocrine hormones, which are signaling compounds that circulate through the general circulation – the bloodstream as we usually think of it – and tell some other tissue, or cells in other tissues from which – in tissues that are not the same tissues that are secreting that signaling compound – tell those other tissues what to do, or tell the cells within those tissues what to do. So if you have insulin, for example, it's made by the pancreas in response to various factors, especially carbohydrate intake. And then it's circulating through the blood and then it's telling cells in other tissues such as adipose tissue, such as the brain, such as skeletal muscle – it's telling them to do certain things in response to the perceived needs of the body as a whole. But then those cells that are supposed to respond to that hormone, they have their own needs and they have their own priorities. And so the cell has to survey all of these different signals coming from outside itself, and then it needs to take that information and incorporate it into a model that includes information from inside the cell about the needs, the abilities and the priorities of that cell for its own survival, whether to respond and how to respond to those hormones. And it's not so much that the cell is being selfish in this regard, as much as it is that the – it's in the interests of the body for the cells to protect themselves, because if all of the cells are going to obey the commands of circulating hormones to their own detriment, then all of the cells can die, because they're trying to unselfishly meet the needs of the body, and then the body's going to be like, oh crap, kinda don't have any cells anymore, what am I going to do? So in making this executive decision, I believe that one of the main drivers of insulin response is cellular energy overload, such that the cell says yes, I see these signals that are telling me that it's in the body's interest for me to take in more energy and to do something with that energy such as store it or metabolize it, so that it can produce useful fuel. But at this particular time, in this particular context I don't have the capacity to take in any more energy in a healthy way, and therefore I am not going to take it in.

10:05 The limitations of using blood insulin and glucose concentrations as a primary metric of insulin resistance are similar to the limitations of assessing your level of “boss resistance” by the number of phone calls you decline from your boss when you skip work.

Now, before we get into the molecular mechanisms underlying this, I want to just take a moment to draw another analogy to help emphasize the limitations to looking at something like, does a cell become less sensitive to insulin when there's more insulin lying around? So let's make an analogy where you are in a job position and you have a boss. And your boss is kind of like insulin, and you're kind of like the cell that's becoming resistant. So let's say that you have a job to do, but there's a particular day where you have a family priority, or you're sick and you can't go to work. And you know that your boss can kind of – let's say – get into your business a little bit more than you would like. But, you know, however much you value this job, you consider it much more important that you attend this family activity, or that you get over the cold you have, or whatever. And so you take the day off, but then your boss calls you and says that he or she needs something from you. And naturally, you decline the phone call. So we could say that you're becoming somewhat boss-resistant. Now, if your state is generally that – okay, you're not going to accept your boss's calls, and if your boss calls you twice and we're measuring your degree of boss resistance by how many phone calls you ignored from your boss, then we're going to say that you're twice as boss-resistant as we would say you were if you only ignored one phone call. And if your boss calls you 10 times and you ignore all those calls, we're going to say that you're 10 times more boss-resistant. Because our metric of how boss-resistant you are is, how many phone calls do you ignore from your boss? And your boss calls 20 times, we're going to say that you're all that much more boss-resistant. But in fact nothing has changed about you. You haven't gotten any more or less sick, and your family priority in the other case hasn't gotten any more or less important to you.

12:25 Why your pancreas is sort of like your boss.

All of the change is a function of your boss. And so your pancreas is kind of like your boss, in a sense. One of the many things that insulin does – one of the many things, I want to emphasize, that insulin does is to help you take up more glucose into your cells. So the pancreas is surveying the need to do this based on blood glucose, partly. Then it's going to secrete more insulin in response that blood glucose. But if the cell has decided that it can't take up any more glucose, then of course the cell is going to become more insulin-resistant, if our metric of insulin resistance is how much insulin is there circulating that you're not responding to. But that doesn't necessarily tell us that the cell has changed in any particular way. Similarly, lets – this would be even more important to view it this way if we were looking at a cellular experiment where we take a cell and just dump insulin on it. All the more so since the experimenter is the one deciding how much insulin to dump on the cell, then all the more so are we going to be able to see more and more insulin resistance the more insulin that you dump on the cell. But that's not – all that's telling us is how much insulin did the researcher decide to dump on the cell; it's not necessarily telling us the internal priorities of the cell have changed.

Now it could be the case that the internal priorities of the cell are all about glucose and insulin. And in that case you could say, well, alright, that's true but if the cell is just deciding that it can't handle any more glucose, then what difference does it make – the main driver of this principle is still that the cell has too much glucose. And so that's where it becomes important to get into the molecular mechanism of this process. So, what factors go into this decision?

14:37 Reactive oxygen species (ROS) are central to the physiology.

Well, I'm not going to pretend that everything comes down to any one particular molecule, but one of the most important and central drivers of this response is reactive oxygen species within the cell. And we could say reactive oxygen species, we could say ROS, we could say oxidants – several ways to communicate the same basic principle. But we're talking about things like superoxide, we're talking about things like hydrogen peroxide. Some of these things are free radicals – superoxide is, hydrogen peroxide is not. So it's more accurate to say reactive oxygen species than to say free radicals. Now in the cell there are a number of sources of reactive oxygen species, but one of them – and the one that I think is most important in this context is the mitochondrion. And the mitochondrion, its primary mode of action you could say in making ATP is to take oxygen and turn it into water, and in that process, extract energy from the electrons that come from the food that we eat and make ATP. Now it is always the case that some portion of that oxygen – generally the minimal amount would be maybe a 10th of a percent, will be converted into superoxide, which is a reactive oxygen species or ROS. And most of that superoxide will be relatively quickly converted into hydrogen peroxide. And so in this context, it's probably mostly hydrogen peroxide that's going to actually have the effects I'm going to describe, simply because there's so much more of it and it's much longer-lived than superoxide is.

Now, hydrogen peroxide and superoxide together are going to communicate the burden of energy that's placed on the mitochondrion. And since there is always some being produced that always has the physiological effects I'm going to describe, we could say that there is some tone set under normal circumstances of energy balance, where there's a very small amount of reactive oxygen species produced that are communicating this normal balance of energy. When too much energy is placed on the mitochondrion, then the proportion and the amount of superoxide will be increased. So at the high end of the spectrum, you may have half a percent of the oxygen being converted into superoxide – that's a five-fold increase in the proportion. And you may also have more oxygen being consumed during that context, and so even greater burden of total superoxide production. And that's primarily going to spill over into more hydrogen peroxide being produced. And so what are the effects of hydrogen peroxide that communicate this energy balance?

17:52 ROS inhibit aconitase and shunt internal energy toward fat storage.

Well, the first thing that hydrogen peroxide is going to do is inhibit an enzyme in the TCA cycle called aconitase. Several episodes ago I talked a bit about the TCA cycle, and if you want to review that material you can go to ChrisMasterjohnPhD.com/22. In any case, in the TCA cycle you have acetyl groups that are taken from glucose, that are taken from fatty acids, that are taken from certain amino acids – it doesn't really matter what macronutrient you're burning for energy, once you get down to the acetyl group everything is all the same. And that acetyl group will come and condense with oxaloacetate and you'll makes citrate. Now, the next enzyme that metabolizes citrate is called aconitase, and it has a cluster of iron and sulfur that allows it to sense the oxidative stress within the cell. And if you have reactive oxygen species being made in the mitochondrion, well the enzyme aconitase is also in the mitochondrion, so it's very close together. And one of the first things that that hydrogen peroxide would do would be to oxidize the iron-sulfur cluster in aconitase and inhibit that enzyme. And so that would prevent citrate from being further broken down for energy. If that happens, citrate accumulates and it moves from the mitochondrion into the cytosol, which is the main aqueous portion of the cell. And when it arrives there, it becomes the substrate for fatty acid synthesis. So the very first reaction to an elevation of hydrogen peroxide is going to be that whatever energy you have coming in, regardless of whether it came from fat, protein or carbohydrate, that will be shifted toward fatty acid synthesis, so towards storage instead of toward being broken down fully for energy to make ATP.

19:55 ROS inhibit further intake of energy.

And if that response is adequate to remove the excess burden on the electron transport chain in the mitochondrion, then reactive oxygen species will decline, and everything will sort of go back to normal. So you've equilibrated to this new amount of energy that's being diverted towards fatty acid synthesis and energy storage, but everything is back to normal and you don't need any further response in order to remove that burden from the mitochondrion. But if that doesn't bring reactive oxygen species down to normal, then the reactive oxygen species can defuse further.

20:34 ROS inhibit fatty acid uptake into mitochondria.

And the next place that they'll reach is the outer mitochondrial membrane, where they will inhibit the channels that bring fatty acids into the mitochondrion. Now, this is not the carnitine shuttle, which is on the inner mitochondrial membrane; these are voltage gated ion channels that are in the outside of the mitochondrial membrane. The detail doesn't really matter. The point here is that once you take what energy has already come in and divert it to energy storage, if that's not sufficient, then the next thing you do is stop energy from coming in. And you'll notice here that now we're talking about inhibiting the entry of fatty acids into the mitochondrion. So not only does it not matter whether it was sugar, fat or protein that was generating the excess energy to make reactive oxygen species, but now it also doesn't matter whether you're talking about preventing glucose or fatty acids or whatever from entering into the mitochondrion. So it's non-specific energy overload that's generating more reactive oxygen species, and then it is a non-specific response to that to stop energy from coming in.

21:53 ROS inhibit glucose uptake.

So here you will inhibit the entry of fatty acids. If those reactive oxygen species diffuse further to the plasma membrane, they will inhibit glucose uptake. So you're inhibiting glucose uptake, you're inhibiting fatty acid entry into the mitochondrion, that's just a general response to energy overload that is causing a general lack of uptake of further energy. And that's how the cell protects itself.

Now, it doesn't stop there. The reactive oxygen species will also cause you to make more mitochondria – that's mitochondrial biogenesis.

22:35 ROS increase the expression of the entire antioxidant system and xenobiotic defense system.

They will cause you to increase the expression of the entire antioxidant system and xenobiotic defense system. The antioxidant system includes things like synthesizing more glutathione, synthesizing the enzymes that detoxify reactive oxygen species and convert them into harmless water. It includes – this is not only the antioxidant system, it's also the xenobiotic defense system, and so that's the system that helps you detoxify foreign compounds that don't belong in your body. So this response to reactive oxygen species is not only to store energy when there's too much energy coming into the mitochondrion, and not only to prevent more additional energy from coming into the cell, it's also to increase the capacity of the cell to burn energy and to burn it cleanly. So what you have is a comprehensive suite of reactions to too much energy coming in that are aimed at equalizing the capacity of the cell to burn energy to that burden. And that is partly removing some of the burden, but also increasing the capacity.

Now imagine this is operating in a lean, healthy person. Suppose that one cell is overburdened with energy, and so all of these things are operating in that one cell. It's probably not going to happen to just one cell, but I'm just making this point to illustrate a point. This one cell is acting in this way, you're not going to see a rise in blood glucose or a rise in free fatty acids or anything else like that in the blood, because that energy is just going to be taken over by the other trillion cells.

So if some of the cells are refusing to take up energy, but other cells are just taking up what's left over, then you don't have a pathological environment – what you have is a means of efficiently allocating resources.

24:53 Subbing players on the field in team sports provides a useful analogy to understand why ROS-mediated inhibition of cellular energy uptake is health-promoting when other cells can fill in.

And I think you could make an analogy to team sports. If you have a particular player on the field, or several players on the field that are nearing exhaustion, you don't want them to get injured, you don't want them to drag down the team, you take them off and sub in someone else and all is well and good, nothing has really happened. But suppose that all of the players needed to get taken off the field because they were all at the brink of exhaustion or injury. And in that case you don't really have any choice except to forfeit the game. Well, similarly in the human body, if some of the cells are rejecting energy, no big deal. But if the preponderance of the cells are rejecting energy, then at some point you're going to cross a threshold where more energy is being rejected than other cells can take up, and it's going to be left in the blood. And in the case of glucose, blood glucose is going to rise.

But look at someone who has diabetes and tell me, do they just have high blood sugar? Well, no, they also have high triglycerides; they also have high free fatty acids; they also have high ketones. So if you look at this case of insulin deficiency or insulin resistance – and here, you know, when I talk about cellular energy overload I'm talking about type II diabetes and insulin resistance, I'm not talking type I diabetes. But, you know, you will also see this lack of – this general increase in energy molecules in the blood in type I diabetes as well. But let's just isolate this conversation to type II diabetes. You will see elevations in all of these energy molecules in the blood. And that's reflective of the fact that it's not just glucose that isn't being taken up into the cell, it is also just general refusal of the cell to take up energy.

Now, that doesn't mean that the only thing going on is someone is consuming too many calories. What it means is that the energy coming into the cell is greater than its capacity to store it or to burn it cleanly. And if the preponderance of cells are experiencing that overload, then that's going to be the case where you have a general situation where energy is being left in the blood and not being efficiently taken up and used or stored by those cells. So that's not all about carbs, because any type of energy overload can drive the reactive oxygen species, and because it's not just glucose that's not being taken up into the cell. And it's not just insulin because, for example, when the cell is deciding at the outer mitochondrial membrane not to take in more free fatty acids, that's not really – that's not a response that's mediated by insulin; the effect of insulin is actually to depress fatty acid uptake into the mitochondrion because you get more insulin response to more carbohydrate and that shifts you away from fat-burning towards carbohydrate-burning. So the effect of reactive oxygen species on glucose uptake is antagonizing insulin. The effect of reactive oxygen species at the mitochondrial membrane to reject free fatty acids coming in – that's actually doing what insulin would have done if the cell were responding well to insulin.

28:30 Insulin resistance isn’t all about insulin; some responses to cellular energy overload antagonize insulin; others mimic insulin.

So insulin resistance isn't all about insulin, because insulin resistance – from our own bias of taking this insulin-centric view of insulin resistance, of this general state of energy overload, and our own bias of seeing diabetes as a disease of high blood sugar, which is part of the truth, then we're calling it insulin resistance, but it's just this one facet of a general system of energy overload. And some of the responses are not at all – such as decreased uptake of fatty acids – that's more mimicking insulin than it is antagonizing insulin. And so we only see insulin resistance when we choose to call it insulin resistance and when we choose to use insulin and carbohydrate as the central sort of paradigm through which we are – the central features of the lens through which we are viewing these processes.

Okay, so I told you before that I had a riddle for you and that I would answer the riddle at the end of the podcast. So in answering this riddle, I want to flesh out a little bit more – I'm going to use this riddle to flesh a little bit more of the concepts related to this idea. And what I want you to get by the end of me explaining this riddle is that the effect of oxidants or reactive oxygen species is all about context, and is all about what situation they're communicating. And so I want you to understand that even though I just told – it may seem like I just told you that insulin resistance isn't all about carbs and insulin, it's all about reactive oxygen species. Actually, if we say insulin resistance is all about carbs and insulin, we're missing the forest for a tree; if we say it's all about reactive oxygen species, we might be missing the forest for some of the leaves, or something like that. In fact, what I'm describing to is not all about reactive oxygen species.

30:46 Back to the riddle.

So, let's get onto this riddle. This riddle is: what do obesity, exercise, cigarette smoking and fruits and vegetables all share in common? So let's flesh this out by looking at oxidation in the cell. And let's do them one by one.

31:05 Obesity vs. exercise

So we just talked about cellular energy overload, and we could say that in general that would be associated with obesity. Now, that's not necessarily strictly the case because people with the same level of obesity can have different levels of capacity within the cell to store or burn that energy. But in general, the more adiposity you have, the more likely you have a preponderance of cells that are overloaded with energy. So what I described to you before, then, is more or less – we could say that's attributable to obesity.

Now let's look at exercise. Well in exercise, part of the response that generates fitness is mediated by reactive oxygen species, only the context in which mitochondrial ROS generation happens in exercise is totally different than obesity. But that's not because the ROS is different, that's because one is obesity and one is exercise. So in exercise, instead of creating an energy crisis at the mitochondrial level by putting in too much energy into the system, you have actually have a different type of energy crisis where the demand for mitochondrial activity has increased. Say you are contracting your skeletal muscle at a high rate and you're burning through ATP. That problem is one of an energy deficit, not an energy excess. Because you now need to replete that ATP that you're burning through. So you're telling the mitochondria: hurry up, help out by making lots and lots of ATP.

32:50 AMPK activation makes the net effects of ROS in exercise very different from obesity.

And one of the signals of this energy deficit is that as you burn through ATP, you first burn through the first phosphate bond's energy supply and you make ADP, and then you burn through the second phosphate's energy supplying and you get AMP. And AMP is a signal of a low-energy state relative to the needs of the cell. And AMP activates an enzyme called AMP-kinase or AMPK. And AMPK activates a suite of processes that are all aimed at restoring the energy deficit in the cell. And one of those is to help the cell take up more and more energy.

So, you know, this is pretty simple: if the cell doesn't have enough energy, it takes up more, regardless of insulin. And in fact, if you look at what is the one of the most successful drugs used to treat insulin resistance, it's metformin. And metformin has many effects that begin on the gut and the gut microbiota and penetrate into the brain. But the present state of research suggests that all of them are mediated by stimulating AMPK. So what metformin is doing is mimicking the energy deficit in exercise or fooling the cells into thinking that the person is in a state of energy deficit. And so it's not resolving the energy overload, but it is stimulating some of the physiological processes that would be stimulated by removing the energy overload. And that's part of why it's successful, although I think it would be much better to actually use diet and lifestyle to actually remove the energy overload in that state.

But think about how do you get fitness in response to exercise? Well, the answer is, when you place the burden on the mitochondria to make more ATP, to consume more oxygen to make that ATP, you will increase superoxide and you will increase hydrogen peroxide. But in the case of obesity, the predominant responses to that hydrogen peroxide were to take the excess energy in the cell and convert it into fat and to refuse to take in more energy. You're not going to get those same responses in the case of exercise, because here, although reactive oxygen species would do those things, they would inhibit aconitase and shift excess citrate towards fatty acid synthesis, they would act to decrease fatty acid uptake and decrease glucose uptake. You're overriding those responses by two things. First of all, you don't have an excess of citrate. Yeah, you have more energy coming in, but you're burning through all of it. So you don't have an excess of energy in the cell to drive into fatty acid synthesis. Number two, the energy deficit itself through AMPK as an example is all mitigating, or shall we say totally overriding the signals to decrease energy uptake by telling the cell: no, take up more and more and more energy. So again, the cell's making an executive decision by integrating numerous pieces of information, and one of those pieces of information may be the reactive oxygen species that, in other circumstances, it would take and use for the decision to take up less energy, you have this much stronger signal from AMPK and other means of signaling the energy deficit that are all overriding the less important information from reactive oxygen species and telling the cell: no, regardless of that other information, you must take in more energy.

So you do have reactive oxygen species, but the net synthesis of that information is not leading the cell to decide to take up less energy; it's leading the cell to decide to take up more energy, because you need it.

On the other hand, if you are chronically telling the cell to burn through ATP through exercise, one of the best things that the cell can possibly do is make more mitochondria, because you're signaling that you have a higher need to burn energy, and so what better way to do that to make more mitochondria?

37:30 Micronutrient intake determines whether net effects of ROS support antioxidant defense.

And, you know, what better way to do that than also to ramp up the antioxidant support, because if you're always going to be burning through more energy, then you need the support system to not only burn through more energy, but to burn through that energy cleanly, and that's where the antioxidant support will come in. Now, that will only be the case if you have the nutrients necessary to support the antioxidant defense system.

37:55 Glutathione synthesis depends on both nutrients and insulin sensitivity and stimulation.

So let's come back to obesity. Cellular energy overload is also occurring in the context of a nutrient-poor diet. Then maybe you don't have the nutrients that you need to make glutathione; maybe you don't have the minerals like iron, copper, zinc, selenium and manganese that you need to support the enzymes involved. Or maybe you are deficient in some of those like selenium, zinc and copper, and maybe manganese, and you have too much iron that's making the reactive oxygen species worse through other mechanisms that I'll talk about a future podcast. But the point is that if your nutrition is not correct, then the overwhelming response will be to shut down the incorporation of energy into the cell, and to drive whatever energy you do have into fatty acid synthesis, and you won't get the benefits of increasing antioxidant support. But even if you do have all of the nutrients there to support it, if your cell is not responding to insulin because of energy overload, one of the responses that fails in that case is glutathione synthesis, because insulin is needed – reactive oxygen species are telling the cell you need to make more glutathione; insulin is telling the cell you are able to make more glutathione, because you do have the energy available for that energy-intensive process.

So if in in obesity, in energy overload, you have reactive oxygen species telling the cell you need to make more glutathione, but then you have lack of insulin signaling that's telling the cell you can't make more glutathione, then you may have a net no effect on glutathione, or you may have a net detriment to glutathione. And if you also have this chronic burden of oxidizing glutathione, then everything altogether may be wrecking your glutathione status, even though reactive oxygen species up-regulate glutathione synthesis, the net context of all the effects is to destroy glutathione status.

Whereas in exercise, you have the potential to really support the antioxidant defense system if you also have the nutrient-replete diet. Because you are increasing your insulin sensitivity with the cellular energy deficit, and you have – if you have a good diet, you have all the nutrients coming in. And if you have the right amount of rest and refeeding, then you have enough insulin stimulation to say, okay, the cell has been primed with this idea that it needs more antioxidant support, and now this incoming insulin and this incoming energy is saying we have the abundance that we need to get that glutathione, so now that we're resting and refeeding, let's make it. Let's make that glutathione. Let's make all these enzymes. And so in that case, because the context is the energy deficit, that is then met with resting and refeeding in the context of a nutrient-dense diet, then the response to reactive oxygen species is increased fitness and increased antioxidant support.

41:10 Insulin resistance isn’t all about ROS. It’s about the context in which ROS operate.

So what's different between those two situations? It's not the reactive oxygen species, it's the context that they're communicating. In a lean person, some of the cells being overloaded with energy – those cells make reactive oxygen species, that just communicates that you need to better allocate resources by having those cells not take in energy, having other cells take in the energy. In cellular energy overload associated with obesity, all the cells or the preponderance of the cells are doing this, and the overwhelming context is a pathological context that communicates whole body resistance to taking up energy. What makes those two situations different isn't the existence of reactive oxygen species or that some cells are making more of it. It's that the context they're communicating is a pathological one of energy overload. In exercise, reactive oxygen species do all the same physiological things and they're increasing. But the context they're communicating is not a pathological one of energy overload. It's a temporary energy deficit in the context of a well-rounded diet and lifestyle pattern, where you then replete the energy and beef up the systems that you need to deal with these periodic energy deficits. So in each case, it's not about the reactive oxygen species, it's about the context that's being communicated.

42:30 The net hormetic pro-oxidant effects of fruits and vegetable polyphenols.

Now, let's tie in fruits and vegetables. So the polyphenol compounds that we refer to in fruits and vegetables as antioxidants are in all likelihood acting as pro-oxidants. Now I don't want to give you the impression that all polyphenols are the same. Actually there are thousands of polyphenols, and they all have different physiological profiles for their effects. However, they – in general we can say some things that is true about most of them, and that is true about the main mechanisms by which polyphenols in general support the antioxidant defense system in a human being or in a live animal. But the principle that is generally applicable to polyphenols is, number one, our bodies treat them as toxins. So we absorb a very small percentage of them, because our intestinal cells spit them back out, and most of them don't get absorbed. Then the portion that we do absorb, we treat as toxins. So in the intestines and the liver, we are going to treat them as xenobiotics – a xenobiotic is anything foreign to the body that it detoxifies. So we then take these and we conjugate them in the way that we would conjugate a drug or an environmental toxin, so that we can more easily excrete them back into the bile or into the urine. If it goes into the bile, they go back in the feces, and in the urine of course you pee it out. And then so what's left over is this even tinier fraction of the polyphenols and most often what we're seeing is not even free polyphenols that are circulating in someone's blood, but actually the conjugated forms that were treated by the xenobiotic defense system. And it's probably those that more often than not are mediating the actual physiological effects.

Now, in any case, what then does this tiny portion of polyphenols do? Well, to support antioxidant defense system, probably the main thing that most of them are doing is they are stimulating Nrf2 transcription. And I won't even bother going through what Nrf2 stands for – some people call it N-R-F-2 [NRF spelled out as individual letters]; I'm in the camp that calls it Nrf2 [sounding like nerf 2]. So anyway, Nrf2 is something that under normal conditions that don't involve elevated oxidative stress, most of the Nrf2 is in the cytosol, which is the main aqueous compartment of the cell – the cell water, we could say. And most of that Nrf2 is bound to a protein called Keap1. And Keap1 stands for something but for now let's just think of it as, Keap1 is the thing that keeps Nrf2 in the cytosol and prevents it from going to the nucleus and altering gene transcription. So under normal conditions Nrf2 is being held in the cytosol, and not only is it being held in the cytosol so that it can't affect the genes, but it's also being constantly diverted into degradation. So you're always making some Nrf2; whatever Nrf2 you have doesn't go to the nucleus, and it just goes into – it just gets degraded until you make more, and so on and so forth.

And Keap1 is a sensor of oxidative stress. So if you make reactive oxygen species in the cell, part of that response that you get that I was talking about before to increase the antioxidant defense system is driven by the fact that reactive oxygen species will oxidize Keap1, and that's Keap1's way of saying: oh, woah, hey, there's a problem here, there's oxidative stress here, let me let go of Nrf2 and allow it to go to the nucleus and upregulate all the genes related to antioxidant defense. So what fruits and vegetables do is – I mean the polyphenols within them, what they do is they actually act as oxidants, they oxidize Keap1, and that causes Nrf2 to go into the nucleus and upregulate all the genes related to antioxidant defense.

Alright, now, guess what else does that? Cigarette smoking. So cigarette smoke is loaded with oxidants, and those oxidants upregulate Nrf2.

46:53 The net toxic pro-oxidant effects of cigarette smoking.

Those oxidants, because of that, upregulate glutathione synthesis. But how many of you, if you're trying to improve your diet, would focus on eating more fruits and vegetables, and how many of you would focus on smoking more cigarettes? We treat them very differently. And, you know, maybe there's some politics in this, maybe there's some bias in this, but for the most part I think the evidence and logic is pretty sound. Most people could stand to eat more fruits and vegetables, and most people who smoke could stand to smoke less or quit. And the reason is that in cigarette smoke you get more toxicity, you get more damage than you get Nrf2 response. Whereas in fruits and vegetables, the polyphenols give you more of a Nrf2 response than they give you toxicity. But if you just take a cell and you dump those same polyphenols on the cell at high concentrations, you kill the cells, for sure. However, the reason – the reason that we get low concentrations of polyphenols from a diet rich in fruits and vegetables, and that we get a hormetic response – meaning we get a response to these that is a positive adaptation even though those things are potentially toxic – the reason that our cells are exposed to hormetic concentrations of polyphenols is because we rejected most of them when we ate them. Most of them got passed into the feces, then they came in and we started excreting them as fast as possible. And then some tiny fraction reached our cells. So we treat them as toxins because they are toxins. But the amount of toxicity that they generate is much less than the Nrf2 response that we get that upregulates antioxidant and xenobiotic defense-related genes.

And so when you look at this, I think you can go back and say, well, in our evolutionary history, what were we more exposed to? Well, plant toxins is what our xenobiotic defense system was optimized for. Because we always had plants in our diets, going back throughout our evolution; we didn't always have benzene, and we didn't always have plasticizers, and we didn't always have cigarette smoke. I mean, I don't know – I can't tell you how much smoke our ancestors were exposed to, we had campfires. But I think, you know, when you directly smoke a pack of cigarettes a day, I think you're inhaling probably a lot more smoke than our ancestors would've gotten. Maybe not. In any case, certainly our ancestors were eating a lot of plants, and our defense systems seem to be optimized to that, so when they recognize those plant toxins, we upregulate all our machinery, and we won that battle with the plants in a way that we didn't win it with cigarette smoking, obesity and environmental toxins and drugs.

49:49 Again, net effects of ROS aren’t about ROS; they’re about the context in which ROS operate.

So once again, what these all share in common is oxidation. But you can have some oxidation where the net effect is toxicity; you can have some oxidation where the net effect is ramp up glutathione in antioxidant defense; you can have some oxidation where the net effect is increase your physical fitness; and you can have some oxidation where the net effect is the rejection of energy, that we have narrowed down in our terminology in the way we speak to “insulin resistance”. What is the same about all of those is the oxidation. What is different about all of those is the context.

So when it comes down to it, in my opinion, what makes the cell stop responding to energy? It's not all about carbs, it's not all about insulin, and it's not all about reactive oxygen species. Reactive oxygen species are central mediators of the process, but it is the context that drives the response to those reactive oxygen species. And that context is one of cellular energy overload.

51:00 Nutrient density as a practical strategy in insulin resistance.

So what practically can we do with this? Well, number one, it's going to depend on the person. If you have someone who's eating a nutrient-poor diet and who is not particularly overweight, and maybe is physically active, then it may be the case that fixing the nutrient deficiencies is the number one thing that they need to do. If you have someone who is overweight or obese and who's eating a nutrient-dense diet, throwing more nutrients into the system isn't going to help you. If you have someone who is obese and who is eating nothing but junk food, then you can probably get a lot of benefit by replacing that junk food diet with nutrient-dense foods, even if you don't remediate the obesity, because you have two major problems and you're fixing one of them.

Now there are studies out there, for example, where supplementing with lipoic acid helps – over the course of several weeks, helps lessen insulin resistance. You know, that's probably going to be very context-dependent, because it may be that the missing link for some people is that they're not making enough lipoic acid, and more in the diet is going to help. But the fact is that when you're looking at this, that some of it is about too much energy coming in; some of this is about not enough movement to stimulate burning of that energy; some of it is about not having the nutrients that you need to support the system.

And when you look at those nutrients, there's no way that I could go through in this podcast practical aspects of all of them, because you're talking about protein, you're talking about specific amino acids like glutathione and cysteine, you're talking about foods that have glutathione in them – like lysine and cysteine I mean – you're talking about foods that have glutathione in them, you're talking about foods that have gamma-glutamyl cysteine bonds in them. You're talking about selenium, you're talking about zinc, copper, you're talking about manganese, you're talking about iron – you don't want too much iron, but you don't want not enough iron. You're talking about all the B vitamins: for example, you support the antioxidant system with glucose and to get that energy from glucose to the antioxidant system you need to use niacin, riboflavin, and thiamine. And when you're talking about breaking down energy to get ATP, that supports the antioxidant defense system, because making glutathione requires ATP. So you need all the B vitamins involved in energy metabolism. And that, again, you see thiamine, niacin, riboflavin turn up, as well as other things like lipoic acid and coenzyme Q10, which we make but maybe we don't make enough of.

And when you start realizing how complicated this is, the low-hanging fruit is just to eat a nutrient-dense diet. And that should be focusing on whole foods for that nutrient density, but it should also be focusing on – it should also be diverse, so you're not missing any particular nutrients. And so you should eat animal foods. But your animal foods should be the closest approximation to nose to tail as you can get. So you should include bones. You should include organ meats. Among those, liver is the most important but it would be best to include a diversity of organ meats, and that's why I'm using liverwurst as an approximation of that – I get liver, heart and kidney, that's better than what I can do on my own if I'm trying to put together individual organ meats, but obviously I'm missing some. But whatever you can do to make a sustainable habit to get the closest approximation on a regular basis to eating nose to tail is going to help out a lot. Eating shellfish and if you can tolerate – if you don't have an allergy to them. Eating a lot of leafy greens, if you're not intolerant of salicylates or oxalates or whatever. Within the spectrum of the things that you tolerate, the more diverse your diet is and the more you focus on certain really nutrient-packed foods like organ meats and leafy greens and egg yolks, and the more well-rounded you get so that you don't have to think too much about the missing nutrients, that's going to be the low-hanging fruit in terms of beefing up the nutrient density of the diet.

But none of that is going to help if the – or I should say, that may help part of the way, but you're never going to fix overweight or obesity with throwing more nutrients at the system. You may be fixing part of the problem, but cellular energy overload is driven largely by too much energy coming in. So, now I talked about this with my own experience and made a lot of practical recommendations in ChrisMasterjohnPhd.com/23, where I talked about my own weight loss experience. And one of those things is that you need to put things like stress management and overall health and wellbeing above the weight loss. But there's a difference between accepting that what you weigh – there's a difference between accepting that at this moment you weigh this much and you have this much body fat and that may be what you need at that moment; there's a difference between accepting that – which you really need to do to get anywhere – instead of responding to social pressure and to self-pressure to lose weight, but at the same time there's a huge difference between that and accepting the false fact that no matter how overweight you are, that's okay in the long term.

56:15 Body composition as a practical strategy in insulin resistance.

So gaining better body composition has to be one of the top priorities to fix this, for anyone who's overweight or obese. However, beating yourself up and responding to social pressure is not the way to lose weight. And if you're gaining weight in response to stress, then forcing yourself to lose weight before you have de-stressed is not the proper way to lose weight. So I went into that in detail – ChrisMasterjohnPhd.com/23 – so I won't belabor the point further. But one of the top practical take-home points to this is that you need to find the right long-term strategy to make an improvement in your body composition if you are overweight or you are obese. And that's going to come down to a combined platform of movement – not only for the sake of creating a caloric deficit, but also to provide resistance exercise for the anabolic stimulus that's going to help you preserve lean muscle mass – and it's going to come down to eating enough protein, and it's going to come down to sustaining a caloric deficit in a way that does not cause you to be hungry all the time and does not cause you to have low energy.

And it may be the case that for some people, decreasing the carbohydrate content of their diet is the easiest, most intuitive principle that allows them to create a sustainable caloric deficit over time. And if that's the case, then a low-carbohydrate diet is going to be the most effective way for that individual to improve their body composition. If that's the case, then a low-carbohydrate diet will be effective for that person in helping them recover from insulin resistance. But we have to be careful not to conflate this system of energy – this energy overload that's driving the physiological process here with the amount of insulin in the blood. Now, certainly if you're decreasing carbohydrate intake and your metric of how insulin-resistant you are is based on the concentrations of insulin and glucose in the blood, well of course you're going to find that the low-carbohydrate diet is probably going to be more effective at remediating insulin resistance than other diets are. But, again, the metric – that's like looking at how boss-resistant you are by how many phone calls you ignore from your boss; that doesn't tell you how important it was to you to make sure you get to the family event or how sick you were. So the problem with looking at insulin and glucose in that context is that it's not directly telling us the state of energy overload in the cell. It's telling us about the energy overload in the cell with respect to glucose and insulin circulating the blood, and if that's our only metric then it has the same problem of looking at boss-resistance by the number of declined phone calls.

59:23 Low-carbohydrate diets as a useful practical strategy for body composition, with potential limitations in the long-term because of the importance of carbohydrates for antioxidant defense.

And then we also want to be careful to note that although carbohydrate restriction may be for many people the best way to create the sustainable caloric deficit that causes them to improve their body composition, it's also the case that insulin itself is necessary to support the antioxidant defense system. And so there may be a point where chronic restriction of insulin is eventually – is not translating into a long-term benefit to the antioxidant defense system. And maybe at first it is, because it's removing much of the excess energy burden, but then you hit a point where you have a law of diminishing returns: you've gotten all the benefit that you can get from that, and then what you haven't gotten is enough insulin to now support the antioxidant defense system as optimally as you can. And if you reach that point, then it may make sense then to start including more carbohydrate in the diet.

Alright, that's all I have to say for now. In the future I'll be talking about how to manage iron status and I'll talk more individually how to assess these nutrients – you know, if you've gotten the low-hanging fruit of trying to get a diverse, balanced, nutrient-dense diet, you may still have nutrient deficiencies, but it becomes a whole hour podcast to talk about how you would manage that, and the best thing that you can do is work with a healthcare practitioner who is well-versed in monitoring people's nutritional status. But I will offer a podcast in the future that will be helpful I think both to people who want to manage their own health, as well as healthcare practitioners who want to use best practice for managing those nutrient status. But for now I think this really gets the concept home. I will add that, as I noted before, I think there are additional layers to this. I talked about cellular energy overload; there's a whole other process of tissue-level energy overload that I believe underlies the inflammatory process that creates systemic responses telling cells not to respond to insulin. And I'll talk about that in a future podcast as well. Remember all of the show notes for this episode can be found at ChrisMasterjohnPhD.com/25, and all of the links and resources are there. And all of the podcasts can be found at ChrisMasterjohnPhD.com/podcast. I hope you enjoyed this episode – I appreciate having you in my audience. And with that, signing off, this has been Chris Masterjohn from ChrisMasterjohnPhD.com, and I will see you next episode.

This episode is brought to you by US Wellness Meats. I discovered this company at Paleo f(X) this spring and I fell in love with them as soon as I tried their liverwurst. For years I've known that I feel best when I eat a diversity of organ meats like liver and heart. I have a clearer mind, feel more energetic, and my energy is much more stable between meals. But it is so hard and so time-consuming to make a sustainable habit out of preparing and cooking organ meats. US Wellness liverwurst is 15% heart, 15% kidney, 20% liver, with the remainder grass-fed beef. That's a whopping half organ meat. It takes zero time to prepare, tastes great and finally makes consuming a diversity of organ meats a habit that I can easily sustain. But just because I'm obsessed with their liverwurst doesn't mean it'll turn out to be your favorite. US Wellness makes an even milder braunschweiger that's 35% liver, 65% beef. And if you have a really sensitive palate and just want to get your feet wet with organ meats, their head cheese delivers the mildest taste with 15% heart, 15% tongue, no liver, and the remainder beef. They also sell an incredible array of other meat products in practically any cut you could want, all from animals raised on pasture. Now, this isn't just about high-quality grass-fed meat products that can up your nutritional game and save you time in the morning. It's also about saving money, and that's because I worked out a special deal for you. As a member of my audience, you can go to grasslandbeef.com and order whatever you want, and as long as your total order is at least 7 pounds and, after applying the discount is at least $75, and as long as it’s under 40 pounds, you just enter the promo code “Chris” at checkout. Putting my name in the box earns you 15% off your order, and since you can order up to 39.9999 pounds of meat at that discount, you can potentially save a lot of money. If you're on the fence or not ready for a big order, don't worry. You can use the promo code “Chris” not once, but twice. So, order the minimum your first time, and if you love this stuff as much as I do, order the max the second time around and get the same level of discount. Or just max out your order both times and get just shy of 80 pounds of meat at the discounted price. Either way, head over to grasslandbeef.com and make sure you enter “Chris” at checkout to get the discount.

Alright, if you made it this far, thank you so much for listening. I just have a few more things to share with you before you go. If you love this podcast, please consider supporting it by rating it and reviewing it in the iTunes store. That really helps with the visibility. You can also share it on social media, and you can also find me on social media – Instagram, Twitter, Facebook and Snapchat, and of course you can find the home to all my content at ChrisMasterjohnphdPhD.com. The one thing that you won't find on the website is my newsletter. If you want to sign up for my newsletter, go to ChrisMasterjohnPhD.com/newsletter, and you will get a few emails spaced out by couple days at first just welcoming you to the website and to my vision for it. And then it will transition into a once-a-week insight that I have gained and want to share with you for that week. Finally, if you want to see me speak in person, consider coming to Wise Tradition in Montgomery Alabama November 11 through 14. I hope to see you there if you can make it. And, other than that, that's all I have to share with you today, so I look forward to seeing you in the next episode.

Facebook
Facebook
Twitter
Visit Us
Instagram
SOCIALICON

You may also like

19 Comments

  1. Is it possible that APoE genetics would be important in choosing whether to go low fat, low protein, or low carb in attempting to maintain healthy blood glucose, lipid and also healthy body weight?

  2. Does this also explain then why some studies suggest taking antioxidants (vitamin c/e) around the time of exercise may blunt and be counterproductive to some of the physiological adaptations that happen as a result of exercise (ex. increase cox4).

  3. Hi Chris,

    First of all, thank you for another really great podcast!

    When you talked about about the raised levels of ROS, you suggested that this would be a cause of mithocondrial biogenesis not only from training but also from overeating?

    “Now, it doesn’t stop there. The reactive oxygen species will also cause you to make more mitochondria – that’s mitochondrial biogenesis.”

    As i understand this, this would in time lead to a higher number of mitochondria in obese people? Do you know of any studies showing this?

    I’m interested because im writing my master thesis in muscle physiology at the moment, looking at the morphology of muscle fibres with transmission electron microscopy. So far our earlier data seems to suggest a tendency for fewer mitochondria in obese type 2 diabetics, and therefor i would be very interested in studies contradicting this. Your argument makes so much sense!

    Thank you so much for your time!

  4. “When too much energy is placed on the mitochondrion, then the proportion and the amount of superoxide will be increased. ”

    So, are you saying that the whole problem cascades from excessive energy intake, simply eating too much?

    Wouldn’t excessive energy also be obtained from simple carbohydrates metabolizing too quickly? Creating too much energy for cells to uptake at once?

  5. Hi Chris – you mentioned the possibility at one stage of offering a one on one nutritional approach for individuals. Is that something you are still considering? Thks.

  6. VERY detailed and fascinating insights into insulin resistance. I hadn’t though of it in this broad way.

    It went a long way to explain how Mg deficiency could hold one hostage of IR even though they might have corrected most other contributing factors. In the book The Magnesium Miracle I read that sometimes Mg deficiency alone can trigger insulin resistance. I’m not sure how well researched that statement is, but certainly piqued my interest.

    Ken – have you measured your RBC Mg levels?

    Also – it gives a more solid vision of why exercise is so good at helping break IR.

    Thank you Chris.

  7. Is there something wrong with this website? The main home page (https://chrismasterjohnphd.com/podcast/) doesn’t list any podcasts above 22! I found this page by just trying the ‘/25’ trick in the url.

    In terms of insulin, what would be the primary problem with the idea that a carb-centric diet leads to chronic elevated insulin levels (which may lead to heart disease)?

    Finally, do you have any thoughts on using smart drugs for increased insulin sensitivity? I see antiaging-systems has a couple Metformin products (met-pro, glucophage, etc) that at least according to Dr. Dean Ward, not only help with insulin but act like a smart drug similar to modafinil!

  8. Hey Chris,

    Another great podcast! What are your thoughts about the use of potatoes (ex: the potato hack) and other resistant starches to increase insulin sensitivity ?

  9. Hi Chris, thanks for this super dense informative podcast! I think the analogies are very helpful, albeit a bit overdrawn at points. I especially liked how you juxtaposed smoking – veggies and obesity – excercise, same ROS, completely different outcome.

    I was wondering, how/if nutrient status regulates appetite? I.e. would increasing nutrient density always be a good strategy for the obese? This seems to be the premise of Paleo. Best, Nils

  10. Great talk. Still not sure it explained my mild insulin resistance (too much energy to the cells or oxidative stress?) At age 67, I exercise regularly, I eat a nutrient dense diet, I’m thin and muscular. But, my Hemoglobin A1c is 5.6-5.7, fasting blood sugar is 85-90, last fasting insulin was 7 but CRP is usually below .5 but last test was .8. I also supplement everything that previous metabolic markers showed a possible deficit.
    I’ll checkout the transcript when it comes out. I studied nutrition and admire your grasp of the complex chemistry.

  11. Hello Chris.
    You have talked about energy overload in mitochondria, how in this picture are incorporated uncoupling proteins, who in my understanding can burn excess calories?
    Another question, in the end you mention that energy overload in tissue can cause low level of chronic inflammation. Can give links to articles about these processes?

  12. Want to read this, not listen, sorry Chris!

    Am in the UK. BUT easier to read this stuff.

    Followed you for a long time, including waiting while you regrouped!!
    Many thanks

    1. I support this comment: I prefer to read complex detailed technical information – it is easier to digest
      Thanks

  13. One more question—an “aside” to the show. I’m interested in trying US Wellness liverwurst (I LOVE liverwurst!) as a way to get a range of organ meats into my diet. What is a safe amount per day, or per week, for a 150 lb person?
    I recently had a nutritionist shudder in considering eating organ meats because she’s seen some ethnic groups (I forget which) ruin their health by eating too much organ meat (sorry, I also forget which organs . . .).
    Where is the safe moderation point in ounces per day or week?
    Thanks again! Terry

  14. Hi Chris,
    Do you think Metformin might be used as a short-term solution to increase mitochondria for someone who is unable to exercise, such as with Chronic Fatigue Syndrome (and with no other sugar metabolism issues)? I have normal blood sugar readings but do feel that I easily overeat since my activity level is low (though not bedridden). And I’ve intuitively felt, for years, that getting energy into the cell has something to do with it because now & then a new supplement will “jump start” me for a while (B vits, carnitine, BCAAs, etc), but then I seem to revert back to a low & slow homeostasis. I do eat a nutrient rich diet.
    I wonder if a few months of dosing might build enough mitochondria to help break the cycle enough to tolerate a minimal amount of exercise, which could then be used to break the cycle further?
    Thanks for your good work, Terry

  15. Is it possible that APoE genetics would be important in choosing whether to go low fat, low protein, or low carb in attempting to maintain healthy blood glucose, lipid and also healthy body weight? I have lower fasting blood sugar on high carb low fat almost no meat. Such a puzzle.

Leave a Reply

Your email address will not be published. Required fields are marked *